Independent and Interactive Effects of Tetradecanoyl Phorbol Acetate on Growth and Differentiated Functions of FRTL5 Cells*

Lombardi, Antonio; Veneziani, Bianca Maria; Tramontano, Donatella; Ingbar, Sidney H.

doi:10.1210/endo-123-3-1544

Cited by 57 publications

(23 citation statements)

References 26 publications

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“…Contrary to the TPA attenuation of the TSH-induced stimulation of FRTL-5 cell replication observed by Lombardi and coworkers (25), in our experiments on PC Cl3 cells, TPA did not significantly alter the TSHinduced increase of labeled nuclei. Obviously this cell line-related difference needs to be explored in more depth, particularly using a broad range of TPA concentrations.…”

Section: Discussioncontrasting

confidence: 99%

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Insulin and TSH promote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells

Kimura¹,

Dumont²,

Fusco

et al. 1999

European Journal of Endocrinology

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In the rat thyroid cell lines PC Cl3, FRTL-5 and WRT, proliferation is mainly regulated by insulin or IGF, and TSH. However, the mechanism regulating cell mass doubling prior to division is still unknown. Our laboratory has shown that in dog thyroid cells insulin promotes growth in size while TSH in the presence of insulin triggers DNA replication. In the absence of insulin, TSH has no effect on cell growth. In this report we investigated insulin action on both cell mass and DNA synthesis and its modulation by TSH and insulin in PC Cl3 and FRTL-5 cells. In PC Cl3 cells, insulin activated not only DNA synthesis but also protein synthesis and accumulation. Although TSH potentiated the stimulation of DNA synthesis induced by insulin, enhancement of protein synthesis by both agents was additive. All TSH effects were reproduced by forskolin. Similar effects were also obtained in FRTL-5 cells. This suggests that insulin and TSH, via cAMP, modulate both growth in size and DNA replication in these cell lines.Lovastatin, which blocks 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreased the induction of DNA synthesis, but not of protein synthesis induced by insulin or TSH in PC Cl3 cells. In FRTL-5 cells, lovastatin reduced protein and DNA synthesis stimulated by insulin but not TSH-induced protein synthesis. Taking these data together, we propose that insulin and/or TSH both modulate cell mass doubling and DNA synthesis in these cell lines, presumably via different pathways, and that there are at least two pathways which regulate growth in size in FRTL-5 thyroid cells: one triggered by insulin, which is lovastatin sensitive, and the other activated by TSH, which is not sensitive to lovastatin.

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Section: Discussioncontrasting

confidence: 99%

“…Serum alone induced an increase of the frequency of labeled nuclei, which could be due to EGF, insulin and/or IGF-I (23). FRTL-5 proliferation was enhanced by TPA, as previously shown by some authors (25). By contrast, the PC Cl3 cells did not respond to EGF and serum alone only induced a weak effect.…”

Section: Discussionsupporting

confidence: 84%

Insulin and TSH promote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells

Kimura¹,

Dumont²,

Fusco

et al. 1999

European Journal of Endocrinology

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“…Stimulation of PKC with the phorbol ester TPA, like exposure to v-Ras, induces thyroid cell dedifferentiation (this paper; Lombardi et al 1988). Conversely, depletion of PKC by treatment with high levels of TPA, or inhibition of PKC with sphingosine, overcomes v-Ras and restores TTFl-binding and pTg activity.…”

Section: Pkc Mediates the Effects Of V-rasmentioning

confidence: 98%

v-ras and protein kinase C dedifferentiate thyroid cells by down-regulating nuclear cAMP-dependent protein kinase A.

Gallo¹,

Benusiglio²,

Bonapace³

et al. 1992

Genes Dev.

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Ras proteins are membrane-associated transducers of eternal stimuli to unknown intracellular targets. The constitutively activated v-ras oncogene induces dedifferentiation in thyroid cells, v-Ras appears to act by stimulating protein kinase C (PKC), which inhibits the nuclear migration of the catalytic subunit of the cAMP-dependent protein kinase A (PKA). Nuclear tissue-specific and housekeeping trans-acting factors that are dependent on phosphorylation by PKA are thus inactivated. Exclusion of the PKA subunit from the nucleus could represent a general mechanism for the pleiotropic effects of Ras and PKC on cellular growth and differentiation.

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“…12-O-tetradecanoylphorbol-13-acetatc (TPA). on differentiated thy roid function in vitro [5][6][7], Furthermore, phorbol esters and DAG analogs have differ ent effects on PKC activation [8] and PKC down regulation [9. 10], Recently.…”

Section: Introductionmentioning

confidence: 99%

Effects of the Diacylglycerol Kinase Inhibitor, R59022, on TSH-Stimulated Iodide Organif ication in Porcine Thyroid Cells

Matowe

Ginsberg²

1996

Pharmacology

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We and others have demonstrated that protein kinase C (PKC) activators such as the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), inhibit differentiated thyroid function in vitro. However, phorbol-mediated PKC activation differs from that induced by analogues of the endogenous PKC activator, diacylglycerol (DAG). To explore the effects of endogenous PKC activation on differentiated thyroid function, we examined the effects of the DAG kinase inhibitor, R59022, on TSH-mediated iodide organification in porcine thyroid cells. Following incubation of the thyroid cells for 30 min, 20 and 50 µmol/l R59022 inhibited TSH-stimulated iodide organification by 20 and 41%, respectively. Prolonged exposure (36 h) to R59022 was also studied since similar treatment with TPA downregulates PKC activity. Inhibition of TSH-mediated iodide organification was observed with as little as 5 µmol/l R59022 (56% of control, p < 0.01) with maximal inhibition using 50 µmol/l R59022 to 13% of control values (p < 0.001). To demonstrate that these effects were mediated by PKC activation, PKC isoforms were measured by Western blotting following R59022 exposure (50 µmol/l, 30 min). Increased membrane-bound α- and ζ-PKC isozymes were observed. This is the first demonstration linking specific PKC isoforms to changes in differentiated thyroid function in vitro. The present data suggest that α- and/or ζ-PKC mediate the effects of R5 9022 on differentiated thyroid function in vitro. Further, a PKC inhibitor, chelerythrine (1 µmol/l) was able to partially reverse the effects of prolonged R59022 exposure on TSH-mediated iodide organification. These studies demonstrate that R59022 exposure inhibits TSH-mediated iodide organification in porcine thyroid cells and that these effects are mediated via endogenous PKC activation. These data are consistent with the concept that endogenous PKC acts as a negative modulator of differentiated thyroid function in the porcine thyroid cell.

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Independent and Interactive Effects of Tetradecanoyl Phorbol Acetate on Growth and Differentiated Functions of FRTL5 Cells*

Cited by 57 publications

References 26 publications

Insulin and TSH promote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells

Insulin and TSH promote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells

v-ras and protein kinase C dedifferentiate thyroid cells by down-regulating nuclear cAMP-dependent protein kinase A.

Effects of the Diacylglycerol Kinase Inhibitor, R59022, on TSH-Stimulated Iodide Organif ication in Porcine Thyroid Cells

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